Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GABA (gamma-aminobutyric acid) has a well-known inhibitory effect on the luteinizing hormone-releasing hormone (LHRH) secretion. In order to evaluate the contribution of the catecholaminergic neurotransmitters on the inhibitory effect produced by GABA on the LHRH release, we measured in adult male rats the in vitro hypothalamic output of LHRH, epinephrine (E), norepinephrine (NE) and dopamine (DA); after the administration of, either muscimol 1 microM (GABA-A agonist), and/or 1 microM bicuculline (GABA-A antagonist). The following results were obtained: muscimol inhibited LHRH secretion, and this effect was accompanied by a decrease of NE, E and DA output. The opposite effects were observed after the addition of bicuculline, i.e, stimulation of LHRH, NE, E and DA release. In conclusion, our results show that, in the adult male rats, GABA has an inhibitory effect on the in vitro release of LHRH, acting on the GABA-A receptor. This effect on LHRH secretion might be exerted directly, or indirectly, by altering the release of either NE,E, and/or DA.
Exp Clin Endocrinol Diabetes 1999
PMID:Effects of the GABA-A receptor agonist and antagonist on the in vitro release of hypothalamic catecholamines: apparent parallelism between these effects and the LHRH secretion in adult male rats. 1007 61

The GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) is expressed in pancreatic beta-cells and GABA has been suggested to play a role in islet cell development and function. Mouse beta-cells predominantly express the larger isoform of the enzyme, GAD67, and very low levels of the second isoform, GAD65. Yet GAD65 has been shown to be a target of very early autoimmune T-cell responses associated with beta-cell destruction in the non-obese diabetic (NOD) mouse model of Type 1 diabetes. Mice deficient in GAD67, GAD65 or both were used to assess whether GABA is important for islet cell development, and whether GAD65 is required for initiation of insulitis and progression to Type 1 diabetes in the mouse. Lack of either GAD65 or GAD67 did not effect the development of islet cells and the general morphology of islets. When GAD65-/-(129/Sv) mice were backcrossed into the NOD strain for four generations, GAD65-deficient mice developed insulitis similar to GAD65+/+ mice. Furthermore, at the low penetrance of diabetes in this backcross, GAD65-deficient mice developed disease at the same rate and incidence as wildtype mice. The results suggest that GABA generated by either GAD65 or GAD67 is not critically involved in islet formation and that GAD65 expression is not an absolute requirement for development of autoimmune diabetes in the NOD mouse.
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PMID:Glutamate decarboxylase and GABA in pancreatic islets: lessons from knock-out mice. 1042 32

This study described the effects of GABA agonists on glucose plasma concentrations of streptozotocin-induced diabetic rats. Low doses of an indirect GABA agonist, AOAA (aminooxyacetic acid); a GABA(A) and a GABA(B) agent, THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridone) and baclofen, respectively; and a benzodiazepine were administered to non-diabetic and to diabetic rats. Plasma glucose concentrations were estimated during fasting and after an oral glucose load. Diazepam (1 mg/kg), baclofen (1 mg/kg) and AOAA (30 mg/kg), significantly decreased glycemia after oral glucose overload of streptozotocin-induced diabetes. None of the GABA-acting agents tested changed fasting or glucose overload glycemia of normal rats. Diazepam was the only drug to increase the fasting blood glucose concentration of diabetic rats. Treatment with AOAA or diazepam was accompanied by increased insulin plasma concentrations in diabetic rats to levels similar to the ones of non-diabetic animals. These results demonstrate that benzodiazepines and other GABA drugs act the endocrine pancreas in vivo, ultimately increasing plasma insulin and decreasing high blood glucose levels of diabetic rats. The acute and prolonged effects of the multitude of drugs acting on the GABA(A)-benzodiazepine-chloride ionophore complex remain to be broadly investigated as a therapeutic tool in diabetes.
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PMID:GABA agonists differentially modify blood glucose levels of diabetic rats. 1049 33

1. The effects of streptozotocin (STZ)-induced experimental diabetes on nitrergic-mediated responses to GABA and electrical field stimulation (EFS) have been evaluated in rat isolated duodenum. 2. In the presence of noradrenergic and cholinergic blockade, EFS (60 V, 1 ms, 0.1-32 Hz) induced frequency dependent relaxations of the preparation. GABA also caused submaximal relaxation of the rat duodenum. The relaxations induced by GABA and EFS were reduced in duodenal tissues from diabetic rats compared with control rats. 3. Neither ATP- nor sodium nitroprusside-induced relaxations were altered in diabetic duodenal tissues. GABA- and EFS-induced relaxations were inhibited by NG-nitro-L-arginine methyl ester (L-NAME; 300 mmol/L) in both diabetic and control rats. Although the inhibition caused by L-NAME of GABA- and EFS-induced relaxation was partially reversed by L-arginine (1 mmol/L), L-arginine alone had no effect on GABA- and EFS-induced relaxation in diabetic rats. 4. These results suggest that STZ-induced diabetes impairs non-adrenergic, non-cholinergic relaxation induced by EFS and GABA. Impairment of nitrergic innervation of the rat duodenum may contribute to the abnormalities of intestinal motility abnormalities associated with diabetes.
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PMID:Effects of diabetes on non-adrenergic, non-cholinergic relaxation induced by GABA and electrical stimulation in the rat isolated duodenum. 1049 62

Streptosotocin-induced diabetes in rats is accompanied by the development of diabetic complications such as neuropathies. [2-14C]serotonin and [U-14C]GABA release from the neurotransmitter pre-loaded synaptosomes showed significant elevation. Aldose reductase inhibitors (AL-1576, sorbinil) administration leads to partial restoration of serotonin and GABA release, while picamilon restored only GABA release. It was shown that Na+,K(+)-ATPase activities decreased in synaptosomes, synaptic membranes and sciatic nerve of diabetic rats compared to control. Administration of AL-1576 normalized Na+, K(+)-ATPase activity, while sorbinil and picamilon less effectively. Sorbitol level are increased in streptozotocin-diabetic rats as compared to control. The picamilon and aldose reductase inhibitors administration to diabetic rats is accompanied by the partial reduction of brain sorbitol level. The findings confirm the important role of picamilon and aldose reductase inhibitors in the prevention and treatment of diabetic neuropathy.
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PMID:[Correction of diabetic neuropathies using aldose reductase inhibitors and pikamilon]. 1059 42

Cytokines might play a role in the development of insulin-dependent diabetes. Interleukin 1beta (IL-1beta) has been shown to alter the functional state of insulin-producing beta cells. This effect appears mediated through induction of certain proteins and suppression of others. The present study demonstrates that the ornithine decarboxylase (ODC) activity of rat beta cells and insulin-producing rat insulinoma (RIN) cells increases more than three-fold within 2 h of IL-1beta exposure. Both basal and IL-1 beta induced ODC activities completely disappear following a 2 h block of protein translation. In Western blot analysis, a 51-kDa protein varies in parallel with the ODC-activity. Exposure to IL-1beta increases the 51-kDa band through an effect at the transcriptional level. The higher cellular ODC activity in IL-1beta treated RIN cells is associated with an increased cellular content of its enzymatic product putrescine, but not of putrescine-derived products such as polyamines and GABA. The 30-fold lower ODC activity in rat beta cells forms a technical obstacle to studies on the regulation and functional significance of this enzyme in normal cells. The present findings list ODC-activity as an early response to the effect of interleukin 1beta on the transcriptional activity in insulin-producing cells. Further work is needed to identify whether ODC activation contributes to the previously described functional changes in pancreatic beta cells.
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PMID:Interleukin-1beta induces ornithine decarboxylase activity in insulin-producing cells. 1062 42

1. In the present study, we investigated the effect of GABA and selective GABA agonists and antagonists on neurally induced tracheal contractions in streptozotocin (STZ) diabetic rats. 2. Contractile responses to electrical field stimulation (EFS) in rat tracheal rings were completely abolished by atropine and tetrodotoxin, but were unaffected by the ganglion blocker hexamethonium, indicating that they were mediated via neuronal release of acetylcholine (ACh). 3. Contractions induced by EFS, but not by exogenous ACh, were inhibited by GABA and the selective GABA(B) receptor agonist baclofen, but not by the selective GABA(A) receptor agonist 3-aminopropane sulphonic acid. The inhibitory effects of GABA or baclofen were not affected by the GABA(A) antagonist bicuculline, but were significantly reversed by the GABA(B) antagonist phaclofen. 4. The inhibitory effects of both GABA and baclofen were found to be significantly greater in trachea from control rats compared with tissues from diabetic rats. 5. Non-adrenergic, non-cholinergic relaxation responses elicited by EFS in precontracted tracheal rings from diabetic and control rats were similar in magnitude and were unaffected by GABA or GABA analogues. 6. These results suggest that GABA decreases the response to EFS by directly inhibiting the evoked release of ACh through GABA(B) receptors in rat trachea and that STZ-induced diabetes causes an impairment in the inhibitory effect of GABA on neurally induced contractions in this tissue.
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PMID:Effect of experimental diabetes on GABA-mediated inhibition of neurally induced contractions in rat isolated trachea. 1077 29

Diabetes-associated depression may occur due to changes in the quality of life imposed by treatment, or may be a consequence of the biochemical changes accompanying the disease. It was our objective to evaluate the behaviors of diabetic rats through an animal model of depression, and determine if a positive GABA modulator agent, clonazepam, is an effective antidepressant. Wistar male rats were submitted to the forced-swimming test after 26 days of the induction of diabetes with streptozotocin (60 mg/kg). Test and retest days analyzed with an ethological approach. Clonazepam (control, 0.25, 0. 5, and 1.0 mg/kg) was administered IP 24, 5, and 1 h before the retest. Diabetic rats presented longer immobility duration during test and retest of forced swimming. Diabetic rats dived significantly less during the test. Clonazepam 0.25 and 0.5 mg/kg decreased immobility of diabetic rats with no consequences on the behaviors of nondiabetic rats. These results demonstrate that diabetic rats present more intense depressive-like behavior, such as immobility and lack of interest in exploring the environment, when exposed to the forced-swimming test. It is possible that decreased GABA function is involved in depression associated with diabetes, because a benzodiazepine partially counteracts these changes without modifying blood glucose and glycogen parameters.
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PMID:Ethopharmacology of the antidepressant effect of clonazepam in diabetic rats. 1088 Jun 86

The neurological consequences of diabetes mellitus have recently been receiving greater attention in both clinical and experimental settings. The deleterious effect of hyperglycemia and altered oxidative substrate availability on the diabetic brain is the subject of many studies. The aim of the present study was to examine the effect of the altered metabolic environment, namely, hyperglycemia and hyperketonemia, on glucose metabolism in the diabetic brain. More specifically, we examined the effect of diabetes on the glucose flux via the pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) pathways and subsequent metabolism in the tricarboxylic acid cycles in neurons and glia. To this end, [U-(13)C]glucose was infused into the circulation of alloxan-induced diabetic young adult rabbits, and the [(13)C]glucose metabolites were subsequently studied in brain extracts by (13)C-NMR. Significantly elevated brain glucose levels were found. In the hyperketonemic rabbits, elevated cerebral levels of beta-hydroxybutyrate (beta-HBA) were found. Alterations in the labeling patterns of glutamine in the hyperketonemic group lead to the conclusion that the elevated beta-HBA levels inhibit glucose metabolism, mostly in glia. This results in accumulation of glucose in the diabetic brain. In addition, altered levels of glutamine, glutamate, and GABA were also attributed to the effect of beta-HBA on brain metabolism. The possible role of these metabolic perturbations in causing neurological damage remains to be investigated.
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PMID:Effect of endogenous beta-hydroxybutyrate on glucose metabolism in the diabetic rabbit brain: a (13)C-magnetic resonance spectroscopy study of [U-(13)C]glucose metabolites. 1128 49

Gonadotrophin hormone releasing hormone (GnRH) is the primary messenger involved in sexual maturation and the onset of puberty. The activity of these neurons are controlled by several neurotransmitters systems. The onset of puberty implies changes from a prepubertal type of gonadotrophin secretion, characterized by a low activity of GnRH neurons, to an adult pattern of secretion with phasic and synchronous activation of GnRH neurons resulting in an increase in the amplitute and frequency of GnRH pulses. Neurotransmitter systems are involved in these changes of GnRH secretion during the onset of puberty by quantitative and qualitative modifications in the effect on GnRH secretion. Serotonin (5-HT), GABA and catecholamines (CA) have qualitative differences in the effects on GnRH and LH secretion in early prepubertal than in late prepubertal and adult female rats. The administration of 5-hydroxytryptophan a precursor of serotonin (5-HT) which increases 5-HT hypothalamic levels induces GnRH and LH release in early prepubertal female rats, these effects dissapear in late prepubertal stage having an inhibitory action in adult female rats. GABAergic system also stimulates GnRH and LH secretion in early prepubertal female rats and has an inhibitory action on this axis in late prepubertal period and in adult female rats. On the contrary the inhibition of catecholamines synthesis by alpha-methyl-p-tyrosine induced an increase of LH secretion in early prepubertal female rats and inhibitory effect in late prepubertal and adult stage. These effects indicate tha CA has an inhibitory effects on GnRH-LH secretion in early prepubertal female rats changing to an stimulatory action in the late puberty and adult rats. These qualitative modifications were observed only in female rats and are probably connected with the hypothalamic differentiation into a female type of gonadotrophin control. Opiadergic and excitatory amino acid systems have quantitative differences on GnRH-LH secretion during prepubertal and peripubertal and adult stages. Opiates has an high inhibitory tone in early prepubertal rats that is decreasing during sexual maturation to reach puberty. On the contrary EAA increases its stimulatory activity on GnRH-LH secretion during sexual maturation by increasing the hypothalamic release of aspartate and glutamate, the excitatory amino acids involved in GnRH release, and the sensibility of NMDA receptors to these amino acids. In conclusion sexual maturation and the onset of puberty in the female rats involve qualitative and quantitative modifications in the effects of neurotrasmitters system on GnRH secretion.
Exp Clin Endocrinol Diabetes 2001
PMID:Changes in the control of gonadotrophin secretion by neurotransmitters during sexual development in rats. 1145 30


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